Methods of treating constipation using aminosterol compositions

Abstract

This invention relates to methods of treating constipation and constipation-related symptoms in a subject in need. The methods, which utilize a patient-specific “fixed dose” of an aminosterol, comprise administering a therapeutically effective dose of an aminosterol to a subject in need.

What is claimed is: 
     
         1 . A method of treating, preventing, and/or slowing the onset or progression of constipation and/or a constipation-related symptom in a subject in need comprising administering to the subject a therapeutically effective amount of at least one aminosterol, or a salt or derivative thereof, provided that the administering does not comprise oral administration. 
     
     
         2 . The method of  claim 1 , wherein administering comprises administration selected from nasal, sublingual, buccal, rectal, vaginal, intravenous, intra-arterial, intradermal, intraperitoneal, intrathecal, intramuscular, epidural, intracerebral, intracerebroventricular, transdermal, or any combination thereof. 
     
     
         3 . The method of  claim 1 , wherein administering comprises nasal administration. 
     
     
         4 . The method of  claim 1 , wherein the therapeutically effective amount of the at least one aminosterol or a salt or derivative thereof:
 (a) comprises about 0.1 to about 20 mg/kg body weight of the subject; and/or   (b) comprises about 0.1 to about 15 mg/kg body weight of the subject; and/or   (c) comprises about 0.1 to about 10 mg/kg body weight of the subject; and/or   (d) comprises about 0.1 to about 5 mg/kg body weight of the subject; and/or   (e) comprises about 0.1 to about 2.5 mg/kg body weight of the subject; and/or   (f) comprises about 0.001 to about 500 mg/day; and/or   (g) comprises about 0.001 to about 250 mg/day; and/or   (h) comprises about 0.001 to about 125 mg/day; and/or   (i) comprises about 0.001 to about 50 mg/day; and/or   (j) comprises about 0.001 to about 25 mg/day; and/or   (k) comprises about 0.001 to about 10 mg/day; and/or   (l) comprises about 0.001 to about 6 mg/day administered intranasal; and/or   (m) comprises about 0.001 to about 4 mg/day administered intranasal; and/or   (n) comprises about 0.001 to about 2 mg/day administered intranasal; and/or   (o) comprises about 0.001 to about 1 mg/day administered intranasal.   
     
     
         5 . The method of  claim 1 , wherein:
 (a) the aminosterol or a salt or derivative thereof is taken on an empty stomach, optionally within two hours of the subject waking; and/or   (b) no food is taken or consumed after about 60 to about 90 minutes of taking the aminosterol or a salt or derivative thereof; and/or   (c) the aminosterol or a salt or derivative thereof is a pharmaceutically acceptable grade of at least one aminosterol or a pharmaceutically acceptable salt or derivative thereof; and/or   (d) the subject is human; and/or   (e) the aminosterol is comprised in a composition further comprising one or more of the following: an aqueous carrier; a buffer; a sugar; and/or a polyol compound; and/or   (f) the subject is a member of a patient population or an individual at risk for developing constipation.   
     
     
         6 . The method of  claim 1 , wherein the aminosterol or the salt or derivative thereof is:
 (a) isolated from the liver of  Squalus acanthias ; and/or   (b) squalamine or a pharmaceutically acceptable salt thereof; and/or   (c) a squalamine isomer; and/or   (d) the phosphate salt of squalamine; and/or   (e) aminosterol 1436 or a pharmaceutically acceptable salt thereof; and/or   (f) an isomer of aminosterol 1436; and/or   (g) the phosphate salt of aminosterol 1436; and/or   (h) comprises a sterol nucleus and a polyamine attached at any position on the sterol, such that the molecule exhibits a net charge of at least +1; and/or   (i) comprises a bile acid nucleus and a polyamine, attached at any position on the bile acid, such that the molecule exhibits a net charge of at least +1; and/or   (j) a derivative modified to include one or more of the following:
 (i) substitutions of the sulfate by a sulfonate, phosphate, carboxylate, or other anionic moiety chosen to circumvent metabolic removal of the sulfate moiety and oxidation of the cholesterol side chain; 
 (ii) replacement of a hydroxyl group by a non-metabolizable polar substituent, such as a fluorine atom, to prevent its metabolic oxidation or conjugation; and 
 (iii) substitution of one or more ring hydrogen atoms to prevent oxidative or reductive metabolism of the steroid ring system; and/or 
   (k) a derivative of squalamine modified through medicinal chemistry to improve bio-distribution, ease of administration, metabolic stability, or any combination thereof; and/or   (l) a synthetic aminosterol; and/or   (m) is selected from the group consisting of:   
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         7 . A method of treating constipation and/or a constipation-related symptom in a subject in need, comprising:
 (a) determining a dose of an aminosterol or a salt or derivative thereof for the subject, wherein the aminosterol dose is determined based on the effectiveness of the aminosterol dose in improving or resolving constipation and/or the constipation-related symptom in the subject;   (b) followed by administering the aminosterol dose to the subject for a period of time, wherein the method comprises:
 (i) identifying a constipation-related symptom to be evaluated; 
 (ii) identifying a starting aminosterol dose for the subject; and 
 (iii) administering an escalating dose of the aminosterol to the subject over a period of time until an effective aminosterol dose is identified, wherein the effective aminosterol dose is the dose where improvement or resolution of the constipation-related symptom is observed, and fixing the aminosterol dose at that level in that particular subject; and 
   (c) optionally wherein each defined period of time is independently selected from the group consisting of about 1 day to about 10 days, about 10 days to about 30 days, about 30 days to about 3 months, about 3 months to about 6 months, about 6 months to about 12 months, and about greater than 12 months.   
     
     
         8 . The method of  claim 7 , wherein the aminosterol or a salt or derivative thereof is administered orally, intranasally, or a combination thereof. 
     
     
         9 . The method of  claim 8 , wherein the aminosterol or a salt or derivative thereof is administered orally and:
 (a) the starting aminosterol dose ranges from about 1 mg up to about 175 mg; and/or   (b) the starting oral aminosterol dose is about 25 mg/day; and/or   (c) the dose of the aminosterol or a salt or derivative thereof for the subject following escalation is fixed at a range of from about 1 mg up to about 500 mg; and/or   (d) the dose of the aminosterol or a salt or derivative thereof for the subject following escalation is fixed at a dose of about 1, about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, about 100, about 105, about 110, about 115, about 120, about 125, about 130, about 135, about 140, about 145, about 150, about 155, about 160, about 165, about 170, about 175, about 180, about 185, about 190, about 195, about 200, about 205, about 210, about 215, about 220, about 225, about 230, about 235, about 240, about 245, about 250, about 255, about 260, about 265, about 270, about 275, about 280, about 285, about 290, about 295, about 300, about 305, about 310, about 315, about 320, about 325, about 330, about 335, about 340, about 345, about 350, about 355, about 360, about 365, about 370, about 375, about 380, about 385, about 390, about 395, about 400, about 405, about 410, about 415, about 420, about 425, about 430, about 435, about 440, about 445, about 450, about 455, about 460, about 465, about 470, about 475, about 480, about 485, about 490, about 495, or about 500 mg/day; and/or   (e) the subject experiences moderate constipation or a related symptom, which is defined as a baseline rate of CSBM or SBM in the subject of one or more CSBM or SBM per week, and wherein the starting oral aminosterol dose is from about 10 to about 75 mg/day; and/or   (f) the subject experiences moderate constipation or a related symptom, which is defined as a baseline rate of CSBM or SBM in the subject of one or more CSBM or SBM per week, and wherein the starting oral aminosterol dose is about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 60, about 65, about 70, or about 75 mg/day; and/or   (g) the subject experiences severe constipation or a related symptom, which is defined as a baseline rate of CSBM or SBM in the subject of less than one CSBM or SBM per week, and wherein the starting oral aminosterol dose is at least about 75 mg/day; and/or   (h) the subject experiences severe constipation or a related symptom, which is defined as a baseline rate of CSBM or SBM in the subject of less than one CSBM or SBM per week, and wherein the starting oral aminosterol dose is from about 75 to about 175 mg/day; and/or   (i) the subject experiences severe constipation or a related symptom, which is defined as a baseline rate of CSBM or SBM in the subject of less than one CSBM or SBM per week, and wherein the starting oral aminosterol dose is about 75, about 80, about 85, about 90, about 95, about 100, about 105, about 110, about 115, about 120, about 125, about 130, about 135, about 140, about 145, about 150 about 155, about 160, about 165, about 170, or about 175 mg/day; and/or   (j) the subject experiences severe constipation or a related symptom, which is defined as a baseline rate of CSBM or SBM in the subject of less than one CSBM or SBM per week, and wherein the starting oral aminosterol dose is at least about 175 mg/day; and/or   (k) the dose of the aminosterol or a salt or derivative thereof is escalated in increments of about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, or about 50 mg; and/or   (l) the dose of the aminosterol or a salt or derivative thereof is escalated in about 25 mg increments; and/or   (m) the aminosterol or a salt or derivative thereof is formulated for oral administration in a composition which is a liquid, capsule, or tablet designed to disintegrate in either the stomach, upper small intestine, or more distal portions of the intestine.   
     
     
         10 . The method of  claim 8 , wherein the aminosterol or a salt or derivative thereof is administered intranasally and:
 (a) the starting dose of the aminosterol or a salt or derivative thereof ranges from about 0.001 mg to about 3 mg; and/or   (b) the starting dose of the aminosterol or a salt or derivative thereof is about 0.001, about 0.005, about 0.01, about 0.02, about 0.03, about 0.05, about 0.06, about 0.07, about 0.08, about 0.09, about 0.1, about 0.15, about 0.2, about 0.25, about 0.3, about 0.35, about 0.4, about 0.45, about 0.5, about 0.55, about 0.6, about 0.65, about 0.7, about 0.75, about 0.8, about 0.85, about 0.9, about 1.0, about 1.1, about 1.25, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.75, about 1.8, about 1.9, about 2.0, about 2.1, about 2.25, about 2.3, about 2.4, about 2.5, about 2.6, about 2.7, about 2.75, about 2.8, about 2.9, or about 3 mg; and/or   (c) the dose of the aminosterol or a salt or derivative thereof for the subject following escalation is fixed at a range of from about 0.001 mg up to about 6 mg; and/or   (d) the dose of the aminosterol or a salt or derivative thereof for the subject following escalation is fixed at about 0.001, about 0.005, about 0.01, about 0.02, about 0.03, about 0.04, about 0.05, about 0.06, about 0.07, about 0.08, about 0.09, about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2, about 2.1, about 2.2, about 2.3, about 2.4, about 2.5, about 2.6, about 2.7, about 2.8, about 2.9, about 3, about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8, about 3.9, about 4, about 4.1, about 4.2, about 4.3, about 4.4, about 4.5, about 4.6, about 4.7, about 4.8, about 4.9, about 5, about 5.1, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, or about 6 mg; and/or   (e) the dose of the aminosterol or a salt or derivative thereof for the subject following escalation is a dose which is sub-therapeutic when given orally or by injection; and/or   (f) the dose of the aminosterol or a salt or derivative thereof is escalated in increments of about 0.1, about 0.2, about 0.25, about 0.3, about 0.35, about 0.4, about 0.45, about 0.5, about 0.55, about 0.6, about 0.65, about 0.7, about 0.75, about 0.8, about 0.85, about 0.9, about 0.95, about 1, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, or about 2 mg; and/or   (g) the aminosterol or a salt or derivative thereof is formulated for intranasal administration in a composition which is a dry powder or nasal spray or liquid nasal spray.   
     
     
         11 . The method of  claim 7 , wherein:
 (a) the improvement a subject experiences following treatment is about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95 or about 100%; and/or   (b) the improvement is measured using a clinically recognized scale or tool; and/or   (c) the constipation-related symptom is frequency of bowel movements, and the improvement or resolution comprises a desired rate of complete spontaneous bowel movement (CSBM) or spontaneous bowel movement (SBM); and/or   (d) the constipation-related symptom is frequency of bowel movements, and the improvement or resolution comprises a rate of CSBM or SBM in the subject of one or more CSBM or SBM per week, 2 or more CSBM or SMB per week, or 3 or more CSBM or SBM per week; and/or   (d) the improvement or resolution comprises an increase in bowel activity, an induction of nausea, an induction of secretory diarrhea, or any combination thereof.   
     
     
         12 . The method of  claim 7 , wherein:
 (a) the starting aminosterol dose is based on a baseline rate of complete spontaneous bowel movement (CSBM) or spontaneous bowel movement (SBM) in the subject;   (b) the starting dose of the aminosterol or a salt or derivative thereof is higher if the constipation is severe, where “severe” is defined as less than one CSBM or SBM per week.   
     
     
         13 . The method of  claim 7 , wherein:
 (a) the dose of the aminosterol or a salt or derivative thereof is escalated every about 1 to about 14 days; and/or   (b) the dose of the aminosterol or a salt or derivative thereof is escalated every about 3 to 5 days; and/or   (c) the dose of the aminosterol or a salt or derivative thereof is escalated every about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, or about 14 days; and/or   (d) the dose of the aminosterol or a salt or derivative thereof is escalated about 1×/week, about 2×/week, about every other week, or about 1×/month; and/or   (e) the fixed dose of the aminosterol or a salt or derivative thereof is given once per day, every other day, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, every other week, or every few days; and/or   (f) the fixed dose of the aminosterol or a salt or derivative thereof is given for a few weeks, followed by skipping a few weeks, followed by restarting aminosterol treatment; and/or   (g) the fixed aminosterol dose is incrementally reduced after the fixed dose of aminosterol or a salt or derivative thereof has been administered to the subject for a period of time; and/or   (h) the fixed aminosterol dose is varied plus or minus a defined amount to enable a modest reduction or increase in the fixed dose; and/or   (i) the fixed aminosterol dose is increased or decreased by about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20%.   
     
     
         14 . The method of  claim 7 , wherein:
 (a) the subject is suffering from a disorder of gastrointestinal motility;   (b) the subject is suffering from a condition or disorder selected from the group consisting of chronic idiopathic constipation, Irritable bowel syndrome, Opioid-induced constipation, and Inflammatory Bowel Disease; and/or   (c) the subject is suffering from a neurodegenerative disease; and/or   (d) the subject is suffering from a neurodegenerative disease wherein the neurodegenerative disease is selected from the group consisting of Parkinson's Disease, Alzheimer's disease (AD), Huntington's chorea and/or Huntington's disease, Multiple Sclerosis, Amyotorphic Lateral Sclerosis (ALS), multiple system atrophy (MSA), schizophrenia, Friedreich's ataxia, vascular dementia, Lewy Body dementia or disease, spinal muscular atrophy, supranuclear palsy, fronto temperal dementia, progressive nuclear palsy, Guadeloupian Parkinsonism, spinocerebellar ataxia, autism, dementia of aging, neuropathy of diabetes, peripheral sensory neuropathy, cerebral palsy, epilepsy, diabetic neuropathy, traumatic head and/or spine injury, stroke, and depression.   
     
     
         15 . The method of  claim 7 , wherein the constipation-related symptom is selected from the group consisting of:
 (1) frequency of constipation;   (2) duration of constipation symptoms;   (3) frequency of bowel movements;   (4) fecal incontinence/encopresis;   (5) abdominal pain;   (6) abdominal distension or bloating;   (7) abdominal discomfort;   (8) stomach cramps;   (9) stool consistency;   (10) painful defecation/rectal pain with bowel movement;   (11) rectal burning during or after bowel movement;   (12) rectal bleeding or tearing during or after a bowel movement;   (13) ease of defecation/passing stool;   (14) straining during defecation and/or straining or squeezing to try to pass bowel movements;   (15) incomplete evacuation or bowel movement;   (16) unsuccessful attempts at evacuation;   (17) sensation of incomplete bowel evacuation;   (18) sensation of anorectal obstruction/blockage;   (19) bowel movements that were too hard;   (20) bowel movements that were too small,   (21) change in amount of gas passed rectally;   (22) less frequent bowel movements;   (23) oozing liquid stool;   (24) rectal fullness or pressure;   (25) small stool size;   (26) urge but inability to pass stool; and   (27) personal judgement of constipation.   
     
     
         16 . The method of  claim 15 , wherein the constipation symptom to be evaluated is frequency of bowel movements, and wherein:
 (a) the fixed escalated aminosterol dose causes the subject to have a bowel movement; and/or   (b) the method results in an increase in the frequency of bowel movement in the subject over a defined period of time; and/or   (c) the method results in an increase in the frequency of bowel movement in the subject and the increase in the frequency of bowel movement is defined as:
 (i) an increase in the number of bowel movements per week of about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, and about 100%; and/or 
 (ii) a percent decrease in the amount of time between each successive bowel movement selected from the group consisting of about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%; and/or 
   (d) as a result of the method the subject has the frequency of bowel movement recommended by a medical authority for the age group of the subject; and/or   (e) the starting aminosterol dose is determined by the severity of the constipation, wherein:
 (i) if the average complete spontaneous bowel movement (CSBM) or spontaneous bowel movement (SBM) is one or less per week, then the starting aminosterol dose is at least about 150 mg; and 
 (ii) if the average CSBM or SBM is greater than one per week, then the starting aminosterol dose is about 75 mg or less; and/or 
   (f) wherein each defined period of time is independently selected from the group consisting of about 1 day to about 10 days, about 10 days to about 30 days, about 30 days to about 3 months, about 3 months to about 6 months, about 6 months to about 12 months, and about greater than 12 months.   
     
     
         17 . The method of  claim 7 , wherein the compound is an aminosterol that can inhibit the formation of actin stress fibers in endothelial cells stimulated by a ligand known to induce stress fiber formation, having the chemical structure of Formula I: 
       
         
           
           
               
               
           
         
       
       wherein:
 W is 24S-OSO 3  or 24R-OSO 3 ; 
 X is 3β-H 2 N—(CH 2 ) 4 —NH—(CH 2 ) 3 —NH— or 3α-H 2 N—(CH 2 ) 4 —NH—(CH 2 ) 3 —NH—; 
 Y is 20R-CH 3 ; and 
 Z is 7α or 7β —OH 
 
     
     
         18 . The method of  claim 7 , wherein the aminosterol or the salt or derivative thereof is:
 (a) isolated from the liver of  Squalus acanthias ; and/or   (b) squalamine or a pharmaceutically acceptable salt thereof; and/or   (c) a squalamine isomer; and/or   (d) the phosphate salt of squalamine; and/or   (e) aminosterol 1436 or a pharmaceutically acceptable salt thereof; and/or   (f) an isomer of aminosterol 1436; and/or   (g) the phosphate salt of aminosterol 1436; and/or   (h) comprises a sterol nucleus and a polyamine attached at any position on the sterol, such that the molecule exhibits a net charge of at least +1; and/or   (i) comprises a bile acid nucleus and a polyamine, attached at any position on the bile acid, such that the molecule exhibits a net charge of at least +1; and/or   (j) a derivative modified to include one or more of the following:
 (i) substitutions of the sulfate by a sulfonate, phosphate, carboxylate, or other anionic moiety chosen to circumvent metabolic removal of the sulfate moiety and oxidation of the cholesterol side chain; 
 (ii) replacement of a hydroxyl group by a non-metabolizable polar substituent, such as a fluorine atom, to prevent its metabolic oxidation or conjugation; and 
 (iii) substitution of one or more ring hydrogen atoms to prevent oxidative or reductive metabolism of the steroid ring system; and/or 
   (k) a derivative of squalamine modified through medicinal chemistry to improve bio-distribution, ease of administration, metabolic stability, or any combination thereof; and/or   (l) a synthetic aminosterol; and/or   (m) is selected from the group consisting of:   
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         19 . The method of  claim 7 , wherein:
 (a) the aminosterol is administered in combination with at least one additional active agent to achieve either an additive or synergistic effect; and/or   (b) the additional active agent is administered via a method selected from the group consisting of concomitantly, as an admixture, separately and simultaneously or concurrently, and separately and sequentially; and/or   (c) the additional active agent is a different aminosterol from that administered in the method of  claim 7 ;   (d) the method of  claim 7  comprises a first aminosterol which is aminosterol 1436 or a salt or derivative thereof administered intranasally and a second aminosterol which is squalamine or a salt or derivative thereof administered orally; and/or   (e) the additional active agent is an active agent used to treat constipation or a symptom thereof; and/or   (f) the aminosterol or a salt or derivative thereof is taken on an empty stomach, optionally within two hours of the subject waking; and/or   (g) no food is taken after about 60 to about 90 minutes of taking the aminosterol or a salt or derivative thereof; and/or   (h) the aminosterol or a salt or derivative thereof is a pharmaceutically acceptable grade of at least one aminosterol or a pharmaceutically acceptable salt or derivative thereof; and/or   (i) the aminosterol or a salt or derivative thereof is comprised in a composition further comprising one or more of the following: an aqueous carrier; a buffer; a sugar; and/or a polyol compound.   
     
     
         20 . The method of  claim 7 , wherein:
 (a) the subject is a human; and/or   (b) the subject is a member of a patient population at risk for developing constipation or an individual at risk for developing constipation.